Cancer‐Related Mutations of ERK3 Promote Cancer Cell Invasiveness

Abstract

Extracellular signal‐Regulated Kinase 3 (ERK3) is an atypical member of the mitogen‐activated protein kinase (MAPK) family. Recent studies have shown that ERK3 is highly upregulated in multiple cancers, such as lung cancer and colon cancer. In addition, ERK3 promotes cancer cell migration and invasion, at least partly by upregulating matrix metalloproteinase genes' expression. Gene mutation is a major cause of human cancers. However, little is known about ERK3 mutations in cancer development and progression. By reviewing COSMIC database of gene mutations in cancers, we found two ERK3 mutations L290P and L290V which exist in cancers of lung, large intestine and skin. Notably, ERK3 L290 residue is located in the kinase domain of ERK3 and is conserved in ERK1/2/3/4. In order to characterize these mutations, we generated plasmids for ERK3 with each of these point mutations, and overexpressed them in H1299 and A549 lung cancer cells. We found that in comparison with wild type (WT) ERK3, both of these cancer‐related mutants had greatly increased ability in promoting cancer cell migration and invasion. To elucidate the underlying mechanism by which ERK3 L290 mutants increased cancer cell invasiveness, we examined the kinase activity of ERK3 mutants by in vitro kinase assay. We found that ERK3 L290P and L290V mutants have similar kinase activity to WT ERK3. ERK3 protein is known to shuttle between the nucleus and the cytoplasm, which may alter its function. Interestingly, we found that both L290P and L290V mutations greatly increased the cytoplasmic localization of ERK3 proteins, whereas WT ERK3 is mostly nuclear. We are currently trying to elucidate the molecular mechanisms by which L290P (or V) mutations increase the cytoplasmic localization of ERK3 and its ability in increasing cancer cell migration and invasion. In conclusion, our present study has identified previously unstudied cancer‐related ERK3 mutations and their importance in cancer cell invasiveness.Support or Funding InformationNCI 1R01 CA193264‐01 to Weiwen Long and “Saudi Culture mission” support to Hadel Alsaran.